The present invention relates generally to a treatment for chronic pain in general and neuropathic pain in particular. More particularly, the present invention relates to using agmatine as a treatment for neuropathic pain.
Chronic Pain
A large number of disease states (e.g., cancer, AIDS), inflammatory conditions (e.g., arthritis), metabolic disorders (e.g., diabetes) and injuries (e.g., amputations) can give rise to chronic pain, pain persisting more than a few months; other forms of chronic pain have no known origin and are termed idiopathic. Neuropathic pain, pain deriving from dysfunction of the central or peripheral nervous system, may also be a consequence of damage to peripheral nerves or to regions of the central nervous system, may result from disease or may be idiopathic. The common feature of each of these forms of pain is that a person may endure unrelenting pain that is usually resistant to common forms of analgesic therapy.
Symptoms of neuropathic pain include unusual sensations of burning, tingling, electricity, pins and needles, stiffness, numbness in the extremities, feelings of bodily distortion, allodynia (pain evoked by innocuous stimulation of the skin), and hyperpathia (an exaggerated pain response persisting long after the pain stimuli cease).
Several common causes of neuropathic pain are diabetes, cancer chemotherapy, herpes zoster infection, cervical or lumbar root compression owing to degenerative spine disease, malignant lesions of nerve plexus or root, nerve degeneration, such as from amputation, HIV infection, and lesions of central pain pathways, including spinothalamic tract, thalamus, or thalamic radiations. (Max, 1991).
Additional causes of neuropathic pain include drug-induced, or toxic, neuropathies. For example, anti-virals ddI and ddC commonly cause peripheral neuropathies, as do phenytoin (a seizure medication), isoniazid (a tuberculosis medication), vincristine (a cancer chemotherapeutic agent), high dose vitamins, and folic acid antagonists.
Commonly used analgesics, such as morphine, codeine, tramadol, and aspirin have proven effective by temporarily alleviating neuropathic pain. However, the analgesic effects of these compounds are almost always transient; the vast majority of patients treated with these analgesics; continue to experience pain unless readministered the analgesic.
Both scientific and clinical experience indicate that states of neuropathic pain are difficult to treat chronically with narcotic analgesics (e.g., morphine). Furthermore, both narcotic and some non-narcotic (i.e., clonidine, an alpha-2 adrenergic receptor agonist) analgesics induce contraindicating side effects including constipation (opioid), hypotension (adrenergic), respiratory depression (opioid), pharmacological tolerance (opioid and adrenergic), physical dependence/withdrawal (opioid), sedation (opioid and adrenergic), and dry mouth (adrenergic). These side effect profiles can impact both physician distribution and patient tolerance/acceptance of analgesic therapy using these agents. A number of other substances have also been used with varying degrees of success in the treatment of neuropathic pain. These include the antidepressant amitriptiline, the anticonvulsants carbamazepine, the antiarrythmic drug mexiletine, and the local anesthetics lidocaine and tocaimide; these agents also suffer from limited efficacy or significant side effects. (Dray et al. 1994) The limitations of the current armamentarium of analgesics call for development of non-toxic therapeutics with novel or unidentified mechanisms of action. Along those lines, several patents on such compounds have recently been assigned.
Mayer et al., U.S. Pat. No. 5,352,683, discloses administering non-toxic N-methyl-D-aspartate (NMDA) receptor antagonists, such as dextromethorphan, dextrorphan, or ketamine for the treatment of chronic pain.
Pert et al., U.S. Pat. No. 5,534,495, describes a treatment for non-HIV neuropathic pain by administering an effective amount of a peptide that is capable of blocking the loss, destruction, or dysfunction of the cellular constituents that lead to non-HIV neuropathic pain.
Justice et al., U.S. Pat. No. 5,587,454, discusses the use of omega conopeptides to produce analgesia for certain types of neuropathic pain In which morphine was not expected to produce positive results.
Unlike the prevention by pre-treatment or acute attenuation by post-treatment with the NMDA receptor antagonists (e.g., dextromethorphan, ketamine) described in U.S. Pat. No. 5,352,683, we observe that post-treatment with agmatine produces a chronic and perhaps permanent reversal of pain-related behaviors induced by chemical treatment or spinal nerve ligation.
To assist in the study of neuropathic pain, techniques have been developed to chemically induce allodynia in mice or rats by injection of dynorphin A. (Laughlin et al. 1997 and Vanderah et al. 1996) and mechanically induce allodynia in mice or rats by L5/(L6) spinal nerve ligation. (Kim and Chung 1992; Chung and Chung 1997.)
Agmatine
Agmatine is thought to be an endogenous ligand for the imidazoline receptor (Li. et. al. 1994). In addition, published studies suggest that agmatine also blocks the enzyme neuronal nitric oxide synthase (nNOS) (Galea, 1996) which is selectively found in neurons as well as inducible nitric oxide synthase (iNOS) (Auguet et al. 1995 and Galea et al. 1996), which is induced in immune cells by inflammatory stimuli. Other published studies have found that systemic pre- or co-treatment with agmatine reduces excitotoxin-induced loss of cells in primary cerebellar cultures and animals models of ischemia (Gilad et al. 1996) and Gilad et al., U.S. Pat. No. 5,677,349, describes a treatment for stroke. Although agmatine can antagonize NMDA receptors (Yang and Reis, 1997), we have determined that the doses required for the anti-neuropathic pain therapetic effect claimed herein is maximum far below the dose necessary for blockade of these receptors. This result suggests that other mechanisms are responsible for the therapeutic effects of agmatine that we claim here.